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The Journal of Neuroscience, August 30, 2006, 26(35):8955-8964; doi:10.1523/JNEUROSCI.5356-05.2006

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Behavioral/Systems/Cognitive
Increased Expression of the 5-HT Transporter Confers a Low- Anxiety Phenotype Linked to Decreased 5-HT Transmission

Katie A. Jennings,¹ Merewyn K. Loder,² W. John Sheward,² Qi Pei,¹ Robert M. J. Deacon,³ Matthew A. Benson,¹ Henry J. Olverman,² Nicholas D. Hastie,⁴ Anthony J. Harmar,² Sanbing Shen,² and Trevor Sharp¹

¹Department of Pharmacology, Oxford University, Oxford OX1 3QT, United Kingdom, ²Centre for Neuroscience Research, School of Biomedical Sciences, University of Edinburgh, Edinburgh EH8 9JZ, United Kingdom, ³Department of Experimental Psychology, Oxford University, Oxford OX1 3UD, United Kingdom, and ⁴Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh EH4 2XU, United Kingdom

Correspondence should be addressed to Trevor Sharp, University Department of Pharmacology, Mansfield Road, Oxford OX1 3QT, UK Email: trevor.sharp{at}pharm.ox.ac.uk

A commonly occurring polymorphic variant of the human 5-hydroxytryptamine (5-HT) transporter (5-HTT) gene that increases 5-HTT expression has been associated with reduced anxiety levels in human volunteer and patient populations. However, it is not known whether this linkage between genotype and anxiety relates to variation in 5-HTT expression and consequent changes in 5-HT transmission. Here we test this hypothesis by measuring the neurochemical and behavioral characteristics of a mouse genetically engineered to overexpress the 5-HTT. Transgenic mice overexpressing the human 5-HTT (h5-HTT) were produced from a 500 kb yeast artificial chromosome construct. These transgenic mice showed the presence of h5-HTT mRNA in the midbrain raphe nuclei, as well as a twofold to threefold increase in 5-HTT binding sites in the raphe nuclei and a range of forebrain regions. The transgenic mice had reduced regional brain whole-tissue levels of 5-HT and, in microdialysis experiments, decreased brain extracellular 5-HT, which reversed on administration of the 5-HTT inhibitor paroxetine. Compared with wild-type mice, the transgenic mice exhibited a low-anxiety phenotype in plus maze and hyponeophagia tests. Furthermore, in the plus maze test, the low-anxiety phenotype of the transgenic mice was reversed by acute administration of paroxetine, suggesting a direct link between the behavior, 5-HTT overexpression, and low extracellular 5-HT. In toto, these findings demonstrate that associations between increased 5-HTT expression and anxiety can be modeled in mice and may be specifically mediated by decreases in 5-HT transmission.

Key words: serotonin; serotonin transporter; anxiety; polymorphism; microdialysis; serotonergic

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Received Dec. 15, 2005; revised July 10, 2006; accepted July 10, 2006.

Correspondence should be addressed to Trevor Sharp, University Department of Pharmacology, Mansfield Road, Oxford OX1 3QT, UK Email: trevor.sharp{at}pharm.ox.ac.uk

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